This invention relates to a process for preparing N-formimidoyl thienamycin (II) from thienamycin (III) in reaction with certain substituted and unsubstituted benzyl formimidates (I): ##STR2## wherein A is a non-critical anion such as chloro, bromo, hydrogen sulfate, or an alkyl, aralkyl or aryl sulfonate, wherein the alkyl moiety has 1-6 carbon atoms and the aryl moiety is phenyl, for example; X is independently selected from the group consisting of nitro, halo (chloro, bromo, fluoro, and iodo), loweralkyl having from one to six carbon atoms, phenyl, and phenylalkyl having from 7-12 carbon atoms, and --COOR, wherein R is hydrogen or loweralkyl having from one to six carbon atoms; and n is an integer selected from 0, 1, or 2.
N-Formimidoyl thienamycin and thienamycin are both known antibiotics. See for example U.S. Pat. No. 4,194,047 (Mar. 18, 1980) which discloses N-formimidoyl thienamycin and a method for its synthesis from thienamycin. The present process for the preparation of N-formimidoyl thienamycin (II) proceeds via the reaction of reagent I with thienamycin (III); this reaction is discribed in greater detail below. It should be noted now, however, that the process of the present invention affords the following very important advantages over the prior art preparation of N-formimidoyl thienamycin: (1) The process invention is very efficient in that it may be conducted in dilute aqueous solutions of thienamycin. Since thienamycin is obtained from aqueous fermentation, this feature of the instant process permits the early derivatization of thienamycin without costly concentration and without the attendant intermolecular degradation which has been documented for thienamycin aqueous solutions. (2) Because of the efficiency of the present invention, large excesses of reagent I are not necessary. (3) An advantage related to items (1) and (2) is that use of reagents I in the permissible range minimizes the development of unwanted by-products of reaction which had plagued prior art processes. Typical of such unwanted by-products is the dimer (IV). ##STR3## (4) The instantly employed reagents I are more stable than reagents employed in prior art processes for the preparation of N-formimidoyl thienamycin.
Thus, in summary, this invention provides an efficient conversion of thienamycin to Nformimidoyl thianamycin. The novel reagents I are prepared by treating an etherial suspension of formamide and the appropriate substituted benzyl alcohol with benzoyl chloride. The reagents I in reaction with thienamycin in an aqueous solution at pH 7-8.5 give the desired N-formimidoyl thienamycin. These benzylic formimidate reagents are superior to known alkyl formimidates in he described formimidoylation of thienamycin as they show increased stability in aqueous solution and produce a minimal amount of the undesired bis-thienamycin formamidine by-product. While applicants are bound by no theory, it appears that the success of the instantly disclosed formimidoylation reagents is attributed to the increased lipophilicity of the resulting formimidate (I), thus improving aqueous stability. The use of benzyl and substituted benzyl moieties also provides a means of increasing the leaving group ability of the alcohol moiety, thus minimizing the amount of unwanted by-products. It should be further noted that the prior art procedure of derivatizing thienamycin in a concentrated aqueous solution at pH 8.5 using, for example methylformimidate hydrochloride was beset by disadvantages. The reagent was rapidly hydrolyzed in aqueous solution, thus a large excess (for example 30 equivalents) of reagent was required. Workup of the final reaction mixture gave the desired N-formimidoyl thienamycin contaminated with as much as 15% of the undesired dimer (structure IV above). This unwanted by-product formation coupled with instability of the reagent made this process unattractive.